Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 295, Issue 51, Pages 17413-17424Publisher
ELSEVIER
DOI: 10.1074/jbc.RA120.015595
Keywords
N-glycan branching; N-acetylglucosamine; oligodendrocytes; myelination; myelin repair; multiple sclerosis; N-linked glycosylation; oligodendrocyte; myelin; metabolism; oligodendrocyte precursor cell
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Funding
- Marilyn Hilton innovator award
- NIAID National Institutes of Health [R01AT007452]
- NCCIH National Institutes of Health [R01AI144403]
- Deutsche Forschungsgemeinschaft [Exc. 257]
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Myelination plays an important role in cognitive development and in demyelinating diseases like multiple sclerosis (MS), where failure of remyelination promotes permanent neuro-axonal damage. Modification of cell surface receptors with branched N-glycans coordinates cell growth and differentiation by controlling glycoprotein clustering, signaling, and endocytosis. GlcNAc is a rate-limiting metabolite for N-glycan branching. Here we report that GlcNAc and N-glycan branching trigger oligodendrogenesis from precursor cells by inhibiting platelet-derived growth factor receptor-alpha cell endocytosis. Supplying oral GlcNAc to lactating mice drives primary myelination in newborn pups via secretion in breast milk, whereas genetically blocking N-glycan branching markedly inhibits primary myelination. In adult mice with toxin (cuprizone)-induced demyelination, oral GlcNAc prevents neuro-axonal damage by driving myelin repair. In MS patients, endogenous serum GlcNAc levels inversely correlated with imaging measures of demyelination and microstructural damage. Our data identify N-glycan branching and GlcNAc as critical regulators of primary myelination and myelin repair and suggest that oral GlcNAc may be neuroprotective in demyelinating diseases like MS.
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